The long-term objective of this research proposal is to develop a novel approach to detect and to treat breast cancer. Na+/I- symporter (NIS) is a transmembrane glycoprotein that mediates active iodide uptake in thyroid follicular epithelial cells. Selectively increased NIS expression/function in thyroid tissue is the molecular basis of effective radioiodine treatment for patients with thyroid cancers. Since NIS is highly expressed in lactating breast tissues and the majority of human breast tumors express NIS, we hypothesize that NIS expression/function can be up-regulated in breast tumors enabling targeted radionuclide imaging and therapy. Three specific aims are proposed to identify the factor(s) that will selectively increase NIS expression in breast tumors: Aim 1. Determine the mechanism of NIS up-regulation by human chorionic gonadotropin (hCG), trans-retinoic acid (tRA), and cyclooxygenase-2 (Cox-2) in human breast cancer cells; Aim 2. Investigate NIS regulation by downstream effectors of ras in human breast cancer cells; and Aim 3. Establish pre-clinical mouse models to perform high throughput screening for the factor(s) that will selectively increase NIS expression/function in breast tissues. The success of the proposed study will take us one step closer to proceed to human clinical trials using identified compound(s) to increase NIS expression and function in breast tumors enabling radionuclide to localize and ablate residual breast cancer following mastectomy, such that recurrence and metastasis of the disease can be prevented.